Summary As the number of Alzheimer's disease (AD) patients increases rapidly, a simple and specific blood test to diagnose AD is needed. Our recent research discovered that a single peripheral injection of pramlintide can move amyloid-? peptide (A?) from the brain into the blood in AD mouse models, and the level of A? increase in the blood correlates well with the existing amount of A? in the brain. Based on this finding, the proposed study is to further the development of a blood test for AD patients that we initiated by a single injection of pramlintide as the challenge for biomarker changes in blood. This challenge test will be a diagnostic test for AD similar in principle to the glucose tolerance test that shows abnormalities specifically in diabetic patients. The central hypothesis is that a single pramlintide injection will significantly induce a change in a group of AD-related factors in the blood of AD patients but not in those with normal cognition, and the signature of these changes will correlate with the AD biomarkers in the central nervous system (CNS). We will recruit 240 subjects from 3 clinical research centers to conduct the pramlintide challenge test. There will be three specific aims. Aim 1 is to investigate whether a single injection of pramlintide induces a dose-dependent increase in A? in the blood of AD patients. Aim 2 is to investigate whether the pattern of AD biomarker changes in the pramlintide challenge test correlates with AD biomarkers in CSF. Aim 3 is to determine whether the pattern of AD biomarker changes in the pramlintide challenge test correlate with amyloid burden in the brain. Pramlintide is non-amyloidogenic amylin analog, and is an FDA-approved drug for diabetes with a favorable safety profile. Should our proposed study support the concept of the amylin challenge test as a diagnostic test for AD, this test will be able to be conducted in a doctor's office. 1